Abstract
The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E−07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10−9). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.
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References
Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST . Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013; 57: 1333–1342.
Zignego AL, Giannini C, Monti M, Gragnani L . Hepatitis C virus lymphotropism: lessons from a decade of studies. Dig Liver Dis 2007; 39 (Suppl 1): S38–S45.
Terrier B, Cacoub P . Cryoglobulinemia vasculitis: an update. Curr Opin Rheumatol 2013; 25: 10–18.
Zignego AL, Giannini C, Gragnani L . HCV and lymphoproliferation. Clin Dev Immunol 2012; 2012: 980942.
Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005; 165: 101–105.
Sansonno D, De Vita S, Iacobelli AR, Cornacchiulo V, Boiocchi M, Dammacco F . Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol 1998; 160: 3594–3601.
Zignego AL, Gragnani L, Giannini C, Laffi G . The hepatitis C virus infection as a systemic disease. Intern Emerg Med 2012; 7 (Suppl 3): S201–S208.
Ferri C, Zignego AL, Bombardieri S, La Civita L, Longombardo G, Monti M et al. Etiopathogenetic role of hepatitis C virus in mixed cryoglobulinemia, chronic liver diseases and lymphomas. Clin Exp Rheumatol 1995; 13 (Suppl 13): S135–S140.
Cicardi M, Cesana B, Del Ninno E, Pappalardo E, Silini E, Agostoni A et al. Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C. J Viral Hepat 2000; 7: 138–143.
Ferri C . Mixed cryoglobulinemia. Orphanet J Rare Dis 2008; 3: 25.
Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 2004; 33: 355–374.
Ferri C, Monti M, La Civita L, Longombardo G, Greco F, Pasero G et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 1993; 82: 3701–3704.
Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D, Sollima S et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev 2011; 10: 444–454.
Saadoun D, Asselah T, Resche-Rigon M, Charlotte F, Bedossa P, Valla D et al. Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C. Hepatology 2006; 43: 1337–1345.
De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64: 843–853.
Cacoub P, Terrier B, Saadoun D . Hepatitis C virus-induced vasculitis: therapeutic options. Ann Rheum Dis 2014; 73: 24–30.
Dammacco F, Sansonno D . Therapy for hepatitis C virus-related cryoglobulinemic vasculitis. New Engl J Med 2013; 369: 1035–1045.
Bianchettin G, Bonaccini C, Oliva R, Tramontano A, Cividini A, Casato M et al. Analysis of hepatitis C virus hypervariable region 1 sequence from cryoglobulinemic patients and associated controls. J Virol 2007; 81: 4564–4571.
Invernizzi R, Nano R, Ippoliti G, Girino M, Gerzeli G . Cytochemical study of tetrahydrofolate dehydrogenase in chronic lymphocytic leukemia cells. Haematologica 1983; 68: 742–749.
Monti G, Saccardo F, Pioltelli P, Rinaldi G . The natural history of cryoglobulinemia: symptoms at onset and during follow-up. A report by the Italian Group for the Study of Cryoglobulinemias (GISC). Clin Exp Rheumatol 1995; 13 (Suppl 13): S129–S133.
Lamprecht P, Gause A, Gross WL . Cryoglobulinemic vasculitis. Arthritis Rheum 1999; 42: 2507–2516.
Pozzato G, Burrone O, Baba K, Matsumoto M, Hijiiata M, Ota Y et al. Ethnic difference in the prevalence of monoclonal B-cell proliferation in patients affected by hepatitis C virus chronic liver disease. J Hepatol 1999; 30: 990–994.
Ossi E, Bordin MC, Businaro MA, Marson P, Bonadonna P, Chiaramonte M et al. HLA expression in type II mixed cryoglobulinemia and chronic hepatitis C virus. Clin Exp Rheumatol 1995; 13 (Suppl 13): S91–S93.
Lenzi M, Frisoni M, Mantovani V, Ricci P, Muratori L, Francesconi R et al. Haplotype HLA-B8-DR3 confers susceptibility to hepatitis C virus-related mixed cryoglobulinemia. Blood 1998; 91: 2062–2066.
Hwang SJ, Chu CW, Huang DF, Lan KH, Chang FY, Lee SD . Genetic predispositions for the presence of cryoglobulinemia and serum autoantibodies in Chinese patients with chronic hepatitis C. Tissue Antigens 2002; 59: 31–37.
Amoroso A, Berrino M, Canale L, Cornaglia M, Guarrera S, Mazzola G et al. Are HLA class II and immunoglobulin constant region genes involved in the pathogenesis of mixed cryoglobulinemia type II after hepatitis C virus infection? J Hepatol 1998; 29: 36–44.
Cacoub P, Renou C, Kerr G, Hüe S, Rosenthal E, Cohen P et al. Influence of HLA-DR phenotype on the risk of hepatitis C virus-associated mixed cryoglobulinemia. Arthritis Rheum 2001; 44: 2118–2124.
Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R et al. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med 2013; 158: 235–245.
De Re V, Caggiari L, De Vita S, Mazzaro C, Lenzi M, Galli M et al. Genetic insights into the disease mechanisms of type II mixed cryoglobulinemia induced by hepatitis C virus. Dig Liver Dis 2007; 39 (Suppl 1): S65–S71.
Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 2010; 466: 113–117.
Tazi-Ahnini R, Cork MJ, Wengraf D, Wilson AG, Gawkrodger DJ, Birch MP et al. Notch4, a non-HLA gene in the MHC is strongly associated with the most severe form of alopecia areata. Hum Genet 2003; 112: 400–403.
Kochi Y, Yamada R, Kobayashi K, Takahashi A, Suzuki A, Sekine A et al. Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences. Arthritis Rheum 2004; 50: 63–71.
Valdes AM, Thomson G, Consortium TDG . Several loci in the HLA class III region are associated with T1D risk after adjusting for DRB1-DQB1. Diabetes Obes Metab 2009; 11 (Suppl 1): 46–52.
Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A et al. Genes mirror geography within Europe. Nature 2008; 456: 98–101.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.
Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR . Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 2012; 44: 955–959.
Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA et al. A map of human genome variation from population-scale sequencing. Nature 2010; 467: 1061–1073.
Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 2010; 42: 436–440.
Marchini J, Howie B, Myers S, McVean G, Donnelly P . A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 2007; 39: 906–913.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Acknowledgements
This study was supported in part by research funding from Merck (to DLT and PD), through the National Institutes of Health, R01DA013324 (to DT) and the Office of AIDS Research. The REVELL study was funded by a grant from the National Heart, Lung and Blood Institute (R01HL076902). This work was supported in part by the National Institutes of Health (R01 AI060561 to LBD and K08AI075031 to EDC), Center for Translational Science Award (Pilot Grant CCL3001018; to EDC) and Center for Translational Science Award (Grant UL1 RR024143, to Rockefeller University), from the National Center for Research Resources, a component of National Institutes of Health. GML and AYK are supported by grants from the National Institutes of Health (DA033541, AI066345 and AI082630). The work was supported by a Wellcome Trust SCF Grant (WT076991MA) to SIK. The study was funded by AIRC (Associazione Italiana per la Ricerca sul Cancro), by ITT (Istituto Toscano Tumori) and by Fondazione Cassa di Risparmio di Firenze; Dr LG was supported by a fellowship from Fondazione Umberto Veronesi.
Author contributions
ALZ, PC, MV, MC, AM, EDC, LG, BT, VP, LBD, SIK, MPB, GML, AYK, LA and DLT collected data. DLT, GLW, PD and RL designed the research analysis and performed the statistical analysis. RL and DLT designed and performed the targeted genotyping. DLT, GLW, ALZ, LG and PD wrote the manuscript. All authors interpreted the data and revised the manuscript.
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P Cacoub is a board member at BMS, Boehringer Ingelheim, GSK, Gilead, Janssen, MSD, Roche, Servier and Vifor; he is a speaker for Astra Zeneca, BMS, Boehringer Ingelheim, GSK, Gilead, Janssen, MSD, Roche, Servier and Vifor; and he receives grants from BMS, GSK, Gilead, MSD, Roche, Servier and Vifor. The other authors declare no conflict of interest.
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Zignego, A., Wojcik, G., Cacoub, P. et al. Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun 15, 500–505 (2014). https://doi.org/10.1038/gene.2014.41
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DOI: https://doi.org/10.1038/gene.2014.41
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